PROJECT SUMMARY ? CLINICAL CORE The function of the Clinical Core is to recruit and screen patient candidates and control subjects and to fully characterize ME/CFS patients and well-matched control subjects (e.g., medical history, ME/CFS Common Data Elements, etc.). A hallmark symptom of ME/CFS is post-exertional malaise (PEM), or the exacerbation of a patient's symptom complex following exertion beyond their unique threshold. The Clinical Core will obtain physiological data to establish the functional status of both patients and controls using the two-CPET protocol to assess the effects of PEM on functional capacity. The increase of ME/CFS symptoms by a standardized exercise stressor provides researchers with a unique opportunity to evaluate the effects of PEM on a patient's ability to produce energy to do work. This requires two sequential exercise stressors using cardiopulmonary exercise tests (CPET) to first measure baseline functional capacity (maximum energy production) and to exacerbate PEM symptoms, and a second test 24 hours later to measure the effects of exertion on energy production. Physiological data obtained from the CPET will be utilized by the Research Projects and the Integrative Data Analysis Core to examine correlations with results of neuroimaging scans from Project 1, extracellular vesicle content, inflammatory markers and metabolite profiling from Project 2, and gene expression in immune cells from Project 3. The Clinical Core will facilitate sharing of physiological data to the Integrative Data Analysis Core to allow the comprehensive analysis of data from the Clinical Core in conjunction with other data acquired in the Research Projects. The Clinical Core will oversee testing of patients and controls at three different sites in two states (New York, California), which differ in demographics and environmental factors. Subjects will be located in two urban but distinctly different environments (greater New York City and Los Angeles) and in the rural areas of central and Western New York State. Studying patients from different environments will enhance our efforts to recruit a relatively diverse sample and probe site- specific or environment effects as etiologic factors of ME/CFS.